5 and IL-18 in Eosinophil Mediated Pathogenesis of Allergic Diseases T ⁎ Hemanth Kumar Kandikattu, Sathisha Upparahalli Venkateshaiah, Anil Mishra

Cytokine and Growth Factor Reviews 47 (2019) 83–98

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Cytokine and Growth Factor Reviews

journal homepage: www.elsevier.com/locate/cytogfr

Synergy of Interleukin (IL)-5 and IL-18 in eosinophil mediated pathogenesis of allergic diseases T ⁎ Hemanth Kumar Kandikattu, Sathisha Upparahalli Venkateshaiah, Anil Mishra

Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, United States

ARTICLE INFO ABSTRACT

Keywords: Eosinophils are circulating granulocytes that have pleiotropic effects in response to inflammatory signals in the Allergy body. In response to allergens or pathogens, exposure eosinophils are recruited in various organs that execute Eosinophils pathological immune responses. IL-5 plays a key role in the differentiation, development, and survival of eo- IL-5 sinophils. Eosinophils are involved in a variety of allergic diseases including asthma, dermatitis and various IL-18 gastrointestinal disorders (EGID). IL-5 signal transduction involves JAK-STAT-p38MAPK-NFκB activation and Immune responses executes extracellular matrix remodeling, EMT transition and immune responses in allergic diseases. IL-18 is a Th2 responses classical cytokine also involved in immune responses and has a critical role in inflammasome pathway. We recently identified the IL-18 role in the generation, transformation, and maturation of (CD101+CD274+) pathogenic eosinophils. In, addition, several other cytokines like IL-2, IL-4, IL-13, IL-21, and IL-33 also contribute in advancing eosinophils associated immune responses in innate and adaptive immunity. This review discusses with a major focus (1) Eosinophils and its constituents, (2) Role of IL-5 and IL-18 in eosinophils development, transformation, maturation, signal transduction of IL-5 and IL-18, (3) The role of eosinophils in allergic disorders and (4) The role of several other associated cytokines in promoting eosinophils mediated allergic diseases.

Abbreviations: 2-CDA, 2-Chlorodeoxyadenosine; AD, atopic dermatitis; AP-1, activator protein 1; AR, allergic rhinitis; APRIL, A proliferation-inducing ligand; ASC, adaptor protein; BCL-XL, B-cell lymphoma-extra large; Btk, Bruton’s tyrosine kinase; C/EBP, CCAAT/enhancer binding protein; CARD, C-terminal caspase-recruitment domain; CCL, chemokine (C-C motif) ligand; CCR3, CC-chemokine receptor 3; CD, cluster of differentiation; c-fos, FBJ murine osteosarcoma viral oncogene homolog; c-jun, proto-oncogene; CLC, Charcot-Leyden crystal protein; COPD, chronic obstructive pulmonary disease; CRTH2, Chemoattractant receptor homologous molecule expressed on T helper type 2 cells; CXCL, chemokine (C-X-C motif) ligand; CXCR, CXC chemokine receptor; DAMPs, damage-associated molecular patterns; DC, dendritic cell; EC, Eosinophilic cystitis; ECE, eosinophilic cellulitis; ECO, eosinophilic colitis; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EF, eosinophilic fasciitis; EG, eosinophilic gastritis; EGE, eosinophilic gastroenteritis; EGF, epidermal growth factor; EGID, eosinophilic gastrointestinal disorders; EGPA, eosinophilic granulomatosis with polyangiitis; EM, eosinophilic myocarditis; EMT, epithelial-mesenchymal transition; EOE, eosinophilic esophagitis; EP, eosinophilic pneumonia; EPX, eosinophil peroxidase; ERK, extracellular signal-regulated kinase; FcεRI, Fc fragment of IgE receptor I; FGF, fibroblast growth factor; FIP1L1-PDGFRA, factor interacting with PAPOLA and CPSF1-like-1–platelet-derived growth factor receptor; FOXP3, forkhead box P3; Gal-10, galectin-10; GATA, globin transcription factor; GI, gastrointestinal; GM-CSF, granulocyte macrophage-colony stimulating factor; GTPase, guanine binding protein Rac1; HES, hypereosinophilic syndrome; hIL-5Rα, human interleukin-5 receptor alpha; HLA‐DRB4, HLA Class II histocompatibility antigen-DR Beta 4 Chain; HS1, hematopoietic lineage cell-specific protein1; ICAM-1, Intercellular adhesion molecule 1; IFN-γ, interferon gamma; IgE, immunoglobulin E; IkB kinase, inhibitor of nuclear factor kappa-B kinase; IL, interleukin; ILC2s, type 2 innate lymphoid cells; iNKT, invariant natural killer T cells; IRAK, interleukin-1 receptor-associated kinase 1; JAK, Janus kinase; JNK, c-Jun N-terminal protein kinase; LFA-1, lymphocyte function-associated antigen 1; MAPK, mitogen-activated protein kinases; MBP, major basic protein; MPO, myeloperoxidase; MyD88, myeloid differentiation primary response 88; NADPH, nicotinamide adenine dinucleotide phosphate; NFκb, nuclear factor kappa B subunit; NK, natural killer; NLRP3, NLR family pyrin domain containing 3; OVA, ovalbumin; p50, nuclear factor kappa-B P50 Subunit; p65, transcription factor p65; PAMPs, pathogen-associated molecular patterns; PDGFRα, platelet-derived growth factor receptor alpha; PE, pulmonary eosinophilia; PI3K, phosphoinositide-3- Kinase; Pim-1, proto-oncogene serine/threonine-protein kinase-1 Pim-1; PKCζ, Protein kinase C zeta; PMN, polymorphonuclear neutrophils; PU.1, transcription factor PU.1; PYD, pyrin domain; Raf-1, Raf-1 proto-oncogene serine/threonine kinase; Ras, retrovirus-associated DNA sequences; rIL-15, recombinant interleukin-15; rMIL-21, recombinant mouse interleukin-15; Shc, Src homology 2 domain containing transforming protein 1; SHP2, protein-tyrosine phosphatase 2C (PTP-2C); SIGLEC, sialic acid binding immunoglobulin-like lectin; SIGLECF, sialic acid binding Ig-like lectin; STAT, signal transducer and activator of transcription; TARC, thymus and activation-regulated chemokine; TFH cell, follicular helper T cells; TGF-β1, transforming growth factor beta 1; Th2, T helper cell type 2; TLR, toll-like receptor; TNF-α, tumor necrosis factor alpha; TRAF6, TNF receptor associated factor 6; TREG cells, regulatory T cells; VEGF, vascular endothelial growth factor ⁎ Corresponding author. E-mail address: [email protected] (A. Mishra). https://doi.org/10.1016/j.cytogfr.2019.05.003 Received 11 February 2019; Received in revised form 28 April 2019; Accepted 9 May 2019 Available online 10 May 2019 1359-6101/ © 2019 Elsevier Ltd. All rights reserved. H.K. Kandikattu, et al. Cytokine and Growth Factor Reviews 47 (2019) 83–98

1. Introduction eosinophils produce Th2 cytokines (IL-4, IL-5, and IL-13). Eosinophils regulate dendritic cells and Th2 pulmonary immune responses [15]. Eosinophils are likely first observed in 1846 by Wharton Jones and Eosinophils suppress Th17 and Th1 responses via DC regulation. Eosi- named by Paul Ehrlich in 1879, with time they have traditionally nophil products can serve as Th2 adjuvants via DC regulation. considered effector cells in the innate immune system. Eosinophils are Eosinophils also regulate T-cell development in the thymus. granulocytic leukocytes that develop in the bone marrow from plur- Eosinophils recognize PAMPs and defense against viral, parasitic and ipotent progenitors and share many features with neutrophils, in- bacterial infection. Eosinophils and mast cells mutually potentiate in cluding growth and development in the bone marrow. In contrast with asthma and eosinophilic esophagitis. Mast cells support the survival and neutrophils, eosinophils exit the bone marrow and reside in the activation of eosinophils by secreting IL-5. Eosinophil MBP activates bloodstream with a half-life of ˜18 h and migrate to the thymus, gas- mast cells and basophils, and release cytokines, histamine, and TNF-α trointestinal tract under homeostatic conditions. Eosinophils arise from [6]. Eosinophils play a key role in tissue destruction and repair. Epi- hematopoietic CD34+ progenitor cells in the bone marrow and are of thelial cells of various tissues stimulate eosinophil secretion of TGF-β 5% of total white blood cells in healthy subjects. Eosinophils are dis- and fibroblast growth factors and play a role in tissue repair and also tinguished phenotypically by their bilobed nuclei and cytoplasmic promote wound healing [16–19]. granules filled with cytotoxic and immunoregulatory proteins [1]. Adipose tissue residential eosinophils regulate local cytokine milieu Mature eosinophils in the blood are less than 400 per mm3. Eosinophils and glucose homeostasis. Eosinophils play a role in adipose tissue respond to signals from cytokines, chemokines, and other proin- macrophage polarization and glucose metabolism critical for main- flammatory mediators via cell-specific receptors most notably by cy- taining adipose tissue M2 macrophages [20]. Human eosinophils pro- tokine interleukin-5 (IL-5) and the eotaxin chemokines. During eosi- moted dorsal root ganglia neuron branching. Peripheral dorsal root nophilopoiesis, eosinophils acquire IL-5Rα and IL-18Rα on the cell ganglia and airway neurons produce eotaxins to chemoattract eosino- surface and differentiate under the influence of both IL-5 and IL-18 [2]. phils [21,22]. Eosinophils producing nerve growth factor and neuro- Transcription factors play a crucial role in eosinophilic lineage com- trophins regulate neuronal activity [23]. Eosinophils in the GI tract play mitment in the bone marrow to maturation and development of eosi- a role in homeostasis and disease contexts, such as in EGID promoting nophils. Eosinophilic progenitors express C/EBPα, C/EBPε, PU.1, and IgA class-switching, enhancing intestinal mucus secretions, determining GATA-1 and GATA-2 [3]. The increased production of eosinophils is intestinal microbiota and inducing the development of Peyer’s patches observed in various allergic conditions, skin diseases, parasitic infec- [8,10]. tions, and reactions to drugs. Peripheral blood and tissue eosinophilia The current review summarizes the most recent advances in our are hallmarks of parasitic helminth infection chronic asthma and al- understanding on the contributions of IL-5 and IL-18 to the growth, lergic diseases and play a role in host defense [4]. Eosinophils migrate transformation, and maturation of eosinophils to the maintenance of from bone marrow to the specific tissues on exposure with allergens and innate and adaptive immune responses in various allergic diseases. The execute immune responses [5]. Eosinophils display pleiotropic effects review also briefs the current pharmacotherapy available to treat var- such as lymphocyte homeostasis, PMN activation, basophil degranula- ious eosinophil-mediated allergic diseases. tion, mastocytosis, macrophage phagocytosis, Th2/DC’s stabilization, epithelial cell differentiation, neurite outgrowth, fat tissue homeostasis, 2. Eosinophilic constituents glucose metabolism, tissue repair and fibrosis, cardiovascular morbidity, bronchospasm, pathogen defense, antigen presentation, extra- Eosinophil constitutes a wide variety of molecules such as adhesion cellular pathogen trap, parasite antibody-dependent cell mediated cy- molecules, adhesion receptors, apoptosis and signaling factors, che- totoxicity [6]. moattractant receptors, chemokines, cytokine and receptors, Fc re- Eosinophils are key innate regulator cells. Under homeostasis, eo- ceptors, growth factors and its receptors, lipid body contents, lipid sinophils are distributed in the blood, lung, thymus, uterus, adipose mediators and its receptors, pattern recognition receptors, granule-de- tissues, mammary gland, spleen and the lamina propria of the gastro- rived receptors, eosinophil-derived granule proteins, enzymes and re- intestinal (GI) tract [7]. However, under the allergic condition, the active oxygen intermediates. Eosinophils morphology, cell-surface re- mature eosinophils under the influence of IL-5 and eotaxin are released ceptors, and intracellular contents differ between species. Particularly from bone marrow to bloodstream and recruit target tissue and mod- interleukin-5 receptor subunit-α (IL-5Rα) and CC-chemokine receptor 3 ulate immune reactions. Eosinophils also regulate adaptive immune (CCR3), as well as sialic acid binding immunoglobulin-like lectin 8 reactions and modulate lymphocyte recruitment and homeostasis. Th2 (SIGLEC-8) in humans, and SIGLEC-F (also known as SIGLEC-5) in mice. cells produce the cytokine IL-5, which promotes eosinophil production, In addition, eosinophil also has CRTH2 receptor that helps in the re- priming, and survival, and IL-13, which induces local cells to produce cruitment of eosinophils in allergic condition via binding its ligands eotaxins, which attract circulating eosinophils into their niche eosino- [24]. Eosinophilic granular proteins comprises, major basic protein-1 phils and are critical for T-cell homing in the lung. Eosinophil-deficient and -2 (MBP-1, MBP-2), eosinophil peroxidase (EPX), eosinophil ca- ΔdblGATA-1 mice reduced Peyer’s patch development, and T helper cell tionic protein (ECP), eosinophil-derived neurotoxin (EDN), Charcot- cytokine production was observed, highlighting the promoting role of Leyden crystal protein/Galectin-10 (CLC/Gal-10). These are routinely eosinophils on lymphocyte homeostasis [8–10]. Bone marrow eosino- studied as markers of eosinophil activation, and we recently reported phils co-localize with plasma cells during their maturation, secrete the that IL-18 influence in the increase production of these toxic proteins cytokines APRIL and IL-6 and contribute to the survival of bone marrow during allergic condition [2]. plasma cells. B cell process of IgA class switching was recently found to be positively regulated by GI eosinophils in the intestinal tissue [8,10]. 2.1. Major basic protein Eosinophils promote B cell proliferation upon eosinophil activation in mice [11]. MBP comprised more than 50% of the granule protein and localized Eosinophils act as antigen-presenting cells. Eosinophils can present in the core of the eosinophil secondary granules. MBP-1 damages cells antigen to T cells. GM-CSF–treated eosinophils induce antigen-specific by disrupting the lipid bilayer membrane or altering the activity of T-cell clone proliferation [12]. Upon allergen exposure, eosinophils enzymes within tissues [25]. MBP-1 stimulates mediator (histamine) present antigens by costimulation of MHC class II [13,14]. Eosinophils release from basophils and mast cells, activates neutrophils and plate- in the airway lumen migrate to the draining lymph node and promote lets, and augments superoxide generation by alveolar macrophages. antigen-specific T-cell proliferation ex vivo. Eosinophils, alone or via MBP-2 is expressed only in eosinophils and exhibits similar functions in dendritic cells, drive Th2 polarization. Upon allergen stimulation, vitro like MBP-1 [26–28].

84 H.K. Kandikattu, et al. Cytokine and Growth Factor Reviews 47 (2019) 83–98

2.2. Eosinophil peroxidase (EPX/EPO) Fig. 1 and Table 1.

EPO is a heme peroxidase found in eosinophils, and its gene located 3. IL-5 mediated signal transduction and eosinophils development on chromosome 17. Its activities include the oxidation of halide ions to and survival bactericidal ROS, the cationic disruption of bacterial cell walls, and the post-translational modification of protein amino acid residues [29–31]. Interleukin 5 (IL-5) plays a vital role in the activation, terminal EPO also mediates protein nitration in allergic airway inflammation in differentiation, growth and survival of eosinophils at the early stage mice. 3-nitrotyrosine (3NT) formation after allergen challenge is de- and the sites of inflammation. Eosinophils highly express the inter- pendent on EPO activity, particularly in eosinophils [32]. leukin-5Rα on their surface and also release significant amounts of IL-5 [ 67]. IL-5 signals via the IL-5 receptor (R) α chain and β chain (βc) 2.3. Eosinophil cationic protein (ECP) complex [68]. Upon activation, IL-5 signaling is initiated by the α-chain that binds IL-5 with low affinity, and dimerization with the βc-subunit ECP is a basic cationic protein located in the eosinophil primary forms high-affinity receptor [69]. IL-5 activation induces phosphor- matrix and is released during degranulation of eosinophils. ECP possess ylation of a series of cellular proteins such as βc, HS1, Shc, Btk, JAK1, helminth-toxic and ribonucleolytic activities. ECP is assayed as one of JAK2, STAT1, STAT3, STAT5, PI3K, MAPKs. Phosphorylation of these the predictive markers of eosinophil activation in biological fluids in proteins activates down-stream molecules such as Pim-1, c-fos, c-jun, diseases like asthma, bullous pemphigoid severity and outcome NFκb, and thus induce cell survival and proliferation, immune re- [32,33]. ECP exerts cytotoxicity to parasites, bacteria, and virus and sponses and eosinophil number [70–76]. JAK2 is associated with hIL- make pores on the cell membrane and kill the cell by osmotic lysis by 5Rα, whereas JAK1 is associated with hIL-5Rα. JAK1 and JAK2 are the passage of water and other small molecules [34]. activated upon IL-5 stimulation. JAK2 and STAT5 activation are essential for IL-5-dependent signal transduction in eosinophils and B cells 2.4. Eosinophil-derived neurotoxin (EDN) [77,78]. IL-5 also activates, SHP2 and Raf-1 and Raf-1 regulate degranulation. Ras GTPase-ERK activation is vital for IL-5 mediated cell EDN is released from eosinophil granules by cytokines and other survival, and proliferation [79]. The inhibitors for kinases demon- proinflammatory mediators [35]. EDN is an active ribonuclease and strated the role of kinases in eosinophils activation [80]. In eosinophils capable of generating soluble ribonucleotides from insoluble tRNA p38 MAP kinases are activated, whereas its activation is inhibited in [36]. Eosinophils upon activation with bacteria release EDN. Eosino- dying eosinophils [81]. The inhibitor for p38 MAP kinase SB239063 phils in response to Staphylococcus aureus, release EDN [37]. EDN in- abolish lung eosinophilia in mice, another inhibitor SB203580 en- duces production of MMP-9 from the nasal epithelium and involves in hances apoptosis of eosinophils [82,83]. However, there is a concern the pathogenesis of chronic eosinophilic rhinosinusitis [38]. Eosinophil- that these inhibitors might have side effects as they target signaling derived neurotoxin correlated with the disease severity of AD and mechanisms in various cell types. In addition to eosinophil survival, IL- considered as a serum biomarker for disease severity in atopic derma- 5 also inhibits eosinophil apoptosis, via NF-κB mediated induction of titis [39]. BCL-XL and play a role in the survival of eosinophils [84,85](Fig. 2).

2.5. The Charcot-Leyden crystal protein/Galectin-10 (CLC/Gal-10) 4. IL-18 mediated signal transduction in inﬂammation

CLC expression was increased in asthma, allergic reactions, and Interleukin-18 (IL-18) is an 18 kDa pro-inflammatory cytokine has fungal and helminthic infections and related to the histological grade been identified as an IFN-γ-inducing factor, and is a member of the IL-1 and with the number of eosinophils in the lesion of celiac disease pa- family of cytokines and display pleiotropic effects in inflammation and tients and also higher in eosinophilic cystitis [40,41]. CLCs upon their allergic diseases [86]. The pro-IL-18 expression observed in immune phagocytosis by primary human macrophages induce the release of the cells like monocytes, macrophages, dendritic cells, Kupffer cells and IL-1β and activate the NLRP3 Inflammasome. CLC functions as a T cell- also in other cell types like keratinocytes, articular chondrocytes, sy- suppressive molecule in eosinophils [42]. Neutralization of galectin-10 novial fibroblasts and osteoblasts [87]. Human eosinophils isolated partially abrogated the suppressive function of the eosinophils, and from BALF and blood express IL-18 mRNA and protein [88]. Pro-IL-18 recombinant galectin-10 was able to suppress T cell proliferation [43]. is cleaved by caspase1 and form IL-18. IL-18 recognizes heterodimeric The components of eosinophils and their functions are described in IL-18 receptors IL-18Rα and IL-18 Rβ, and signals via MyD88, IRAK,

Fig. 1. Eosinophil constituents.

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Table 1 Eosinophil constituents and function.

Eosinophil constituents Molecules Function Reference

Adhesion molecules Integrins, β1, β2, β7, selectins eosinophil recruitment, T cell proliferation [4,44,45,46] Adhesion receptors LFA1, CR3, CR4, VLA4, CD44, CD62L, PSGL1, CD34 Apoptosis and CD30, CD45, CD52, CD69, CD95 Eosinophil survival and apoptotic cell death [47,48] signaling factors Chemoattractant CCR1, CCR3, CCR4, CCR5, CCR6, CCR8, CCR9, CXCR2, Adhesion of eosinophils to the endothelial cells, [49,50] receptors CXCR3, CXCR4, C5aR, C3aR, FPR1 Chemoattractant to immune cells and the site of allergic inflammation. Chemokines CCL3, CCL5, CCL7, CCL8, CCL11, CCL13, CXCL1, CXCL10, CXCL11, CXCL12 Cytokines and IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-11, IL-12, Activation, proliferation, and maturation of eosinophils. [51] receptors IL-13, IL-16, IL-17, IL-18, IL-25, IFN-γ, GM-CSF, TNF, IL- Induction of inflammatory response, induce 2R, IL-3R, IL-4R, IL-5R, IL-9R, IL-10R, IL-13R, IL-17R, IL- overexpression of adhesion molecules and promote 23R, IL-27R, IL-31R, IL-33R, IFNγR, GM-CSFR, airway remodeling. Fc receptors FcαR, FcγRII, FcεRI, FcεRII, eosinophil survival, degranulation, and generation of [46,52] leukotrienes Growth factors and NGF, PDGF, SCF, VEGF, EGF, TGFα, TGFβ, APRIL, Play role in pulmonary hypertension, allergic asthma, [53,54,55,56,57,58,59,60,61,62] receptors TSLPR, KIT, TGFβR allergic rhinitis, and allergic urticarial–angioedema, allergic inflammation Stimulates T cells, B cell proliferation and differentiation, and eosinophil differentiation from peripheral progenitors, growth and differentiation of mast cell progenitors residing in tissues, wound-healing and tissue remodeling, fibrosis, and tissue repair, extracellular matrix protein deposition, stromal fibrosis and basement membrane thickening. Lipid body contents Leukotriene C4, leukotriene D4, leukotriene E4, Activation of platelets, neutrophils and leukocyte [49,63] Thromboxane B2, Prostaglandin E1, Prostaglandin E2, recruitment and, increase airway reactivity, vascular 15-hydroxyeicosatetraenoic acid, Platelet-activating permeability and induction of bronchoconstriction and factor mediates asthma and allergic rhinitis.

Lipid mediators Leukotriene C4/D4/E4, Eotoxin C4/D4/E4, Prostaglandin

E1,E2,F1α, 5-HETE, 5,15-and 8,15-diHETE, platelet activating factor, Thromboxane B2 Lipid mediators DP2 prostaglandin receptor (CRTH2), DP1 prostaglandin receptors receptor, EP2 prostaglandin receptor, Leukotriene B4 receptor, Platelet-activating factor receptor Pattern recognition Dectin-1, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, Recognition of self, bacterial, viral and fungal signals. [64] receptors TLR9, TLR 10, NOD1, NOD2, RIG-1, RAGE Activation of immune responses and release of pro‐inflammatory chemokines, cytokines, granule proteins, leukotrienes, and reactive oxygen species. Activation of the adhesion system and cellular trafficking. Play a role in airway inflammation and hyper‐reactivity. Granule-derived Major basic protein (MBP)-1, MBP-2, Eosinophil Local tissue damage, mast cell and basophil [26,51] proteins peroxidase (EPO), Eosinophil-derived neurotoxin (EDN degranulation, airway mucus production and elevation or RNase2), Eosinophil cationic protein (ECP or RNase3) of reactive oxygen species Enzymes β-glucuronidase, matrix metalloproteinase 9, α- Aid in the migration of eosinophils through basement [48,65] mannosidase, Phospholipase A2, 5-lipoxygenase, 15- membranes, tissue remodeling, degrade phospholipids lipoxygenase, leukotriene C4 synthase, lysozyme, NADPH of Gram-negative bacteria and to cause airway oxidase, Acid phosphatase, collagenase, arylsulphatase B, inflammation and smooth muscle contraction, defense histaminase, phospholipase D, catalase, nonspecific of microorganisms esterase,

Reactive oxygen O2,H2O2, hydroxyl radicles, singlet oxygen Induce inﬂammatory response and T cell proliferation [66] intermediates

TRAF6 and degradation of IκB kinase and phosphorylates p50 and p65 (Fig. 5). NLRP3 inflammasome responses drive steroid-resistant asthma complexes and induces NFκB signal transduction. On the other hand, IL- [39]. NLRP3 inflammasome formation is observed in the development 18 mediated TRAF6 also phosphorylates MAPK, ERK, and JNK and of COPD and many other inflammatory diseases [96]. induce AP-1 activation. These responses play a role in IL-18 mediated immune activation of T cells, B cells, NK cells, macrophages, mast cells and dendritic cells (Fig. 4). IL-18 mediated Th1/Th2 response leads to 5. Role of IL-18 in eosinophils development and maturity B-cell activation via the release of cytokines IFNγ and IL-4 [89,90]. Infection with pathogens like bacteria, virus, and fungi, and irritants Previously, Ougura et al. [97] described that IL-18 induces neu- exposure like silica, asbestos, and bleomycin, challenge activates trophils, eosinophils, and lymphocytes with an elevation in IL-5 and fi NLRP3 inflammasome via PAMPS and DAMPs in immune cells and GM-CSF levels. Most recently, we rst time implicated the role of IL-18 ff ff increase IL-1β secretion [91–94]. NLRP3 activation involves activation in eosinophils di erentiation and transformation of IL-5 di erentiated + + of adaptor protein ASC, and its sequestration in the nucleus to cytosol naïve eosinophils into the CD101 CD274 pathogenic eosinophils that interact with NLRP3 through its PYD and with caspase-1 through [98]. We showed that eosinophil subsets are not present in naïve IL-18 fi its CARD domains (9, 57). Activated caspase-1 cleaves IL-1β and IL-18, gene-de cient mice and an increase in the human blood and tissues in in the cytoplasm and these cytokines are released to the extracellular diseases state. Importantly, IL-18 is induced in most allergic disease and milieu and activate NLRP3-TLR-MYD88-NFκB signal transduction [95] all eosinophils accumulated in the tissues of allergic patients are expressing CD101+CD274 [98].

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Fig. 2. IL-5 mediated cell signaling in eosinophils.

In addition, Kumano et al. [99] earlier showed that Interleukin-18 interventions for eosinophils associated allergic diseases. enhances eosinophil deposition in the airways of mice immunized and sensitized with oval albumin. Further reports showed the role of IL-18 in eosinophil-mediated tumoricidal activity against a Colo-205 carci- 7. Eosinophils mediate immune responses noma cell line by upregulating LFA-1 and ICAM-1, however neutralization of IL-18 reduced eosinophil-mediated Colo-205 apoptosis In general eosinophils defense helminth parasites by the release of and inhibited cell-cell adhesion [100]. IL-18 is critical cytokine in- cytotoxic granular proteins via degranulation mechanism [108]. Neu- volved in activation of iNKT cells and ICAM in promoting human EoE, trophils infiltrate to the site of allergen exposure or inflammation. Eo- additionally IL-18 in vitro also stimulates human iNKT cells and en- sinophil major basic protein stimulates PI3K and PKCζ and releases dothelial cells and induce eosinophil-active cytokines IL-5 and IL-13 superoxide via activation of NADPH oxidase [109]. MBP also enhance [101]. We previously reported that IL-18 induce iNKT cell activation to neutrophil adherence receptor CR3, thus enhance the inflammatory release the eosinophil activating cytokine IL-5, as IL-5-deficient mice role of neutrophils in allergic diseases [110]. The transmembrane mi- and iNKT cell-deficient (CD1d null) mice do not induce EoE in response gration of eosinophils was observed upon coincubation of eosinophils to intranasal IL-18 challenge. Thus allergen-induced IL-18 has a sig- with neutrophils and stimulation with IL-8, and this provides evidence nificant role in promoting IL-5 and iNKT dependent EoE pathogenesis in that neutrophils migrate in response to IL-8 and leads to eosinophils mice [102]. IL-18 overexpression induces Th1, Th2 cytokine-mediated accumulation in the airways in asthma [111]. Classical M1 type mac- airway inflammation in mice with an increase in IFN-γ, IL-13, eotaxin rophages are proinflammatory and are activated by IFN-γ and LPS and levels and CD4+ T cells in ova sensitized mice [103]. release IL-12, IL-6, TNF-α, and CXCL10, CCL3. Alternatively, M2 macrophages exhibit anti-inflammatory activity and are activated by Th2 cytokines IL-4 and IL-13 via induction of STAT6 activation and release 6. Importance of IL-5 and IL-18 in eosinophils biology cytokines in asthma and allergic diseases [112,113]. Depletion of alveolar macrophages increased eosinophils in bronchoalveolar lavage IL-5 is a well established eosinophils differentiation, growth, and fluid of ovalbumin (OVA)-sensitized mice model of asthma, and transfer survival factor for eosinophils. Previous studies demonstrated that IL-5 of unsensitized alveolar macrophages abrogated these changes [114]. levels were increased in asthma, allergy, and inflammation [104–106]. IL-33 differentiates eosinophils from CD117+ progenitors in IL-5 de- Thus IL-5 selectively affects eosinophil biology and is involved in a wide pendent manner and enhances airway inflammation with an increase in variety of allergic/inflammatory diseases mediated by eosinophils and eosinophils and macrophages [115]. is a therapeutic target for eosinophil-associated diseases. Mast cells interact with eosinophils on IgE activation or dex- Role of IL-18 in asthma development was studied in a model of amethasone challenge, and this interaction helps in eosinophils survival airway hyperresponsiveness, and peribronchial eosinophilic in- and communication and mediated by CD48, and 2B4 mediate mast flammation of mice. Administration of mice with anti-human IL-18 cell–eosinophil interactions and increase eosinophil survival [116]. In antibodies protected against eosinophil-mediated airway inflammation another study of allergen-induced EOE model, Niranjan et al. [117], and demonstrated the role of IL-18 in the development of asthmatic identified an increase in esophageal mast cell numbers in parallel with inflammation [107]. The current review signifies the critical synergetic eosinophils and promoted muscle cell hyperplasia and hypertrophy. role of IL-5 and IL-18 in eosinophils transformation from naïve eosi- Mastocytosis and mast cell degranulation observed in the esophagi of nophils to pathogenic eosinophils. These understandings will provide patients with esophageal esophagitis [118]. Mast cell-mediated che- an important input in eosinphils biology and future therapeutic mokine release leads to the recruitment of eosinophils and natural killer

87 H.K. Kandikattu, et al. Cytokine and Growth Factor Reviews 47 (2019) 83–98

(NK) cells, through CCL11 and CXCL8 [119]. Mast cells alone are also able to mediate Th17 mediated allergic reactions independent of eosinophils via IL-33 response in eosinophil-deficient ΔdblGATA mice model following OVA inhalation [120]. Basophils also play a key role in acute and chronic allergic reactions. Basophils secrete IL-4, and IL-13 and promote Th2 dependent immunity [121,122]. Nakashima et al. [123] reported that basophils induce eosinophils upon interaction with mesenchymal fibroblasts in murine irritant contact dermatitis model via reactive oxygen species production. Upon allergen exposure, dendritic cells acquire the allergen and present to the draining lymph node, and the cells mature and induce T cell and B cell responses. Dendritic cell number increase with allergen exposure. Activation of TLR4 leads to DC migration and recruitment and induce Th2 responses [124]. On the other hand, eosinophil recruitment regulated by classical dendritic cells subsets. During memory stage of chronic asthma with allergen exposure in mouse cDC1s secrete CCL17 and CCL22 and recruit eosinophils and promote early eosinophil infiltration, as a part of type 2 immune response by lung CD24−CD11b + DC2s by producing NO on day 1.5, and further this process is inhibited by releasing TGF-β1 on day 2.5 by CD24+ cDC2s [125]. Eosinophils also induce diverse immune responses upon allergen exposure and mediate cellular, humoral immune response and help defense the host immune system. Eosinophils induce Th2 immune response that involves the presentation of antigen to CD4 + T cells and Th2 differentiation, IL-4, IL-13 cytokine release within lymph nodes and tissues and secretion of EDN and recruitment of Th2 to cells under inflammation. Previous studies also demonstrated the central role of Th2 cells and eosinophils in allergic responses, and mice lacking IL-13, a Th2 cytokine and pre eosinophilic cytokine IL-5 neutralization dis- played Aspergillus fumigatus clearance [126]. Eosinophils induce B cell proliferation, survival, antibody secretion and plasma cell maintenance, proliferation, and survival (Fig. 3). IL-5 Tg hypereosinophilic mice with profound B cell expansion showed a decrease in B cell lymphocytosis upon genetic deletion of eosinophils. Also, patients with idiopathic hypereosinophilic syndrome (HES) revealed a correlation between eosinophils levels and circulating B cell numbers [11,127–129]

8. Other cytokines involved in IL-5 and IL-18 mediated Fig. 4. Role of IL-18 in inﬂammation and eosinophil mediated allergic diseases. eosinophilic allergic diseases

Several cytokines play a critical role in allergic reactions, and contribute to disease pathology through the recruitment and activation of

Fig. 3. Production, migration, and recruitment of eosinophils from bone marrow to targeted tissues in eosinophil mediated allergic diseases and activation of innate and adaptive immune responses.

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against helminths and other extracellular parasites. IL-4+ TFH cell counts were increased in eosinophilic polyp tissues. IL-4 and IL-21 were involved in polyp TFH cell–induced IgE production from naive B cells, and nasal IL-4+ TFH cell counts correlated highly with local IgE levels in vivo, nasal IL-4+CXCR5+CD4 + T follicular helper cell counts correlate with local IgE production in eosinophilic nasal polyps [134]. ILC2s promote allergic inflammation, IL-4 production by IL-33-stimulated ILC2s blocks the generation of allergen-specific Treg cells and favors food allergy [135]. Thymic stromal lymphopoietin-elicited basophils promote epicutaneous sensitization to food antigens and sub- sequent IgE-mediated food allergy through Th2 polarization and IL-4 production [136]. Eosinophils were the major IL-4 expressing cell type in the heart during experimental autoimmune myocarditis. Eosinophils drive the progression of myocarditis to inflammatory dilated cardiomyopathy through IL-4 [137].

8.2. IL-9

IL-9 is a Th2-derived cytokine and an important mediator of allergic inﬂammation. IL-9 overexpressing mice show increased mast cell numbers in the intestine with inﬂammation, paneth cell hyperplasia and up-regulation of IL-13-dependent innate immunity mediators in the intestinal mucosa [138]. IL-9 governs allergen-induced mast cell activation, and anti-IL-9 treatment protects from airway remodeling in asthma in mice [139]. Intestinal expression of IL-9 and mast cells are higher in patients with food allergy. In response to IL-33; IL-9-producing mucosal mast cells secrete increased amounts of IL-9 and IL-13 and play a key role in susceptibility to IgE-mediated food allergy [140].

8.3. IL-13

Overexpression of IL-13 in mice promotes asthma and EoE by an IL- 5, eotaxin-1, and STAT6-dependent mechanism and increase eosinophils and epithelial cells hyperplasia [141]. However, it is also reorted that IL-5 has a critical role in promoting IL-13 induced disease pathogenesis [117], because IL-13 gene-deficient mice demonstrated development of allergen-induced EoE. Similarly, a report also indicates that esophageal eosinophilia is observedeven in IL-4/IL-13 double gene- deficient and STAT6 gene-deficient mice. Indicating, that anti-IL-4Rα therapy may not protect allergen or cytokine induced gastrointestinal disorders.

8.4. IL-17

IL-17A and IL-17 F are Th17 cytokines produced by CD4+ T cells Fig. 5. Role of IL-18 and inflammasome mediated NFκB activation and immune and implicated in the pathogenesis of various allergic and chronic in- fl responses in in ammation. flammatory diseases. IL-17+ cell population was found exclusively in CD3+CD4+ T cells, and the percentage of Th17 cells increased in pro-inflammatory molecules and also mediated pro-fibrotic/remodeling peripheral blood of AD patients [142]. IL-17 levels elevated in mouse events. T helper (Th) cells develop from naïve CD4+-T cells under upon allergen exposure, and IL-17 knockout mice attenuated in- lineage-specific culture conditions and release cytokines that play flammation with a significant decrease in eosinophils [143]. IL-17 le- pleiotropic effects in allergic diseases. Th2 cells produce IL-4, IL-5, IL-9, vels elevated in mice infected with the respiratory syncytial virus and IL-13 and play a role in the protection against helminths. Th17 cells during OVA-induced allergic airway inflammation [144]. produce IL-17A, IL-17 F, IL-22 and show activity on neutrophils, macrophages, B-cells and protect from bacteria, fungi and play a role in 8.5. IL-21 chronic inflammatory and autoimmune disorders [130,131]. Th22 cells production of IL-22 plays a role in adaptive immune response [132]. IL- IL-21 is a member of the type I cytokine family and is produced by 18 and IL-33 are involved in the activation of both Th1 and Th2 re- CD4+ T cells, natural killer T cells, and Th17 cells and plays a major sponses and have an important role in promoting adaptive immunity role in the control of innate and adaptive immune reactions [145]. An [133]. increase in serum IL-21 levels in adult atopic dermatitis patients with acute skin lesions was observed in patients [146]. rIL-21 nasal admin- 8.1. IL-4 istration ameliorated allergic rhinitis by prevention of IgE production by B cells, eotaxin production by fibroblasts and attenuation of eosi- IL-4 is produced by Th2 cells, basophils, mast cells, and eosinophils nophil infiltration into nasal mucosa [147]. Indicating anti-IL-21 may and regulates allergic conditions and the protective immune response be effective in eosinophilic allergic patients.

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8.6. IL-22 exacerbations [162]. We most recently showed that CD101+CD274+ pathogenic eosinophils accumulate in the nasal lavages of asthma and IL-22 play a role in inflammations, allergic diseases, and auto- esophageal biopsies of eosinophilic esophagitis patients, respectively. immunity. IL-22 is mainly produced by innate lymphoid cells, not by Th Additionally, these IL-18 responsive eosinophil subsets are also in- cells in the inflamed lungs [148]. IL-22 in lesioned skin of chronic AD is creased in the blood of asthma and eosinophilic esophagitis patients higher than in psoriatic lesions [149]. IL-22 elevated in asthma patients [2]. A similar observations are also reported in the mouse models of and the mouse model of asthma [150,151]. Allergen-sensitized IL-22- asthma and eosinophilic esophagitis. deficient mice suffer from significantly higher airway hyperreactivity upon airway challenge with an increase in eosinophil infiltration, 9.2. Atopic dermatitis (AD) or eczema lymphocyte invasion and production of CCL17 (TARC), IL-5 and IL-13 in the lung. IL-22 play a role in pathogen elimination and innate lung Atopic dermatitis or eczema is one of the most prevalent skin dis- defense against Aspergillus fumigatus mediated by Dectin-1-dependent order and often occurs in children and also may appear in adulthood. IL-22 production [152]. AD is genetical or occurs on exposure with allergens and or environmental factors that involve immune dysregulation and impaired skin 8.7. IL-25 barrier function and results in red itchy and dryness of the skin [163]. The allergens that enter the skin might be picked via IgE receptor by IgE IL-25-high subset people had high Th2 cytokine levels serum IgE, specific antigen bound to Langerhans cells, and these cells migrate to with airway and blood eosinophils, airway hyperresponsiveness, and lymph node and stimulate Th1 cells to differentiate to Th2 cells and subepithelial thickening [153]. IL-25 neutralization in allergen-exposed promote differentiation of B cells to plasma cells and also induce che- mice exhibited a reduction in pulmonary eosinophilia and levels of Th2 mokines, cytokines IL-4, IL-5 and IL-13 and IL-18 release and aid in associated cytokines, IL-5 and IL-13 and decreased fibrosis, airway eosinophil development and release [164]. Pathogenic eosinophilia has smooth muscle hyperplasia and airway hyperreactivity [154]. been shown to be present in patients with AD [165]. Activated eosinophils in turn also secrete cytokines and chemokines, such as IL-16, IL- 8.8. IL-33 12, TGF-β1, and IL-13 and induce immunological reactions. Eosinophil granular proteins deposition and its degranulation observed in AD pa- IL-33 is a nuclear cytokine that belongs to the IL-1 family and plays tients [166]. Topical calcineurin inhibitors like tacrolimus, pimecro- a crucial role in innate immunity. IL-33 expressed in epithelial cells, limus, immunomodulatory agents prednisolone, systemic steroid- lymphoid organs and its levels increased in allergic inflammation and sparing agents azathioprine, methotrexate, cyclosporine, mycopheno- bronchial asthma [155]. Upon allergen challenge IL-33, levels were late are available treatments for AD [167,168]. increased with IL-5 and IL-13 production and airway eosinophilia without T or B cells via CD25+CD44hi lymphoid cells, and this innate 9.3. Anaphylaxis type-2 response abolished in IL-33 gene-deficient mice [156]. Anaphylaxis is a life-threatening hypersensitive reaction. The most 9. IL-5 generated and IL-18 transformed pathogenic eosinophil common allergic reactions of anaphylaxis are exposure to wasp and bee mediated allergic diseases venom, legumes, animal proteins, insect stings, and analgesic medications. The persons that come across anaphylaxis require immediate Allergy is a condition that the body responds abnormally to foreign administration of epinephrine and medical attention. Mast cell sig- substances. This is due to the hypersensitivity of a person’s immune naling via FcεRI and IgE binds to FcεRI, and IgE and antigen-induced system to a particular or a variety of allergens in the environment. The signaling events induce immunological reactions and mediate eosino- common allergens include pollen, bee stings, certain foods, dust, mites, phil-mediated allergic reactions [169]. Glucocorticosteroids, anti- molds, drugs, latex, dander, exposure to animals, and seasonal climate histamines, methylxanthines, venom immunotherapy considered for change. The common symptoms associated with exposure to allergens the management of anaphylaxis [170]. include rashes on skins, eczema, hives, edema, inflammation, rhinitis, sneezing, itching, runny/stuffy nose, cough, chest tightness, wheezing 9.4. Hay fever or allergic rhinitis or shortness of breath, watery, red or swollen eyes (conjunctivitis) and mucus formation. Allergic rhinitis affects 400 million people worldwide [171]. On Allergic diseases affect approximately 50 million Americans and exposure with allergens such as pollens, grass, and dust mites result in a several people worldwide. The common allergic diseases include runny nose, and watery eyes with inflammation of the nose and mucous asthma, atopic dermatitis or eczema, anaphylaxis, hay fever, sinusitis, membranes, fever and the condition referred allergic rhinitis (AR). AR urticaria or hives, and eosinophilic esophagitis. Eosinophil mediated is part of a systemic inflammatory process and is associated with other allergic diseases listed in Fig. 6. inflammatory disorders of mucous membranes including asthma, rhinosinusitis, and allergic conjunctivitis. High prevalence of asthma is 9.1. Asthma recorded in people with persistent and severe rhinitis [172]. Upon sensitization, to allergens, dendritic cells present allergens to T lym- Asthma is narrowing of airways due to inflammation and an ex- phocytes and promote Th2 responses and activate CD4+ T cells and cessive mucous generation that results in coughing, wheezing, chest releases IL-4, IL-5, IL-10, and IL-13 cytokines. IL-4 induces IgE class tightness and shortness of breath. Eosinophilic function in asthma is not switch in B lymphocyte and release IgE in the bloodstream that binds clear, and all the asthmatic patients are not eosinophilic. Preclinical with mast cells and basophils. Mast cells release histamine and mediate models of lung allergy delineated that mice lacking eosinophils still nasal response. Histamine and TNF-α, leukotriene C4 and prostaglandin develop airway hyperreactivity [157–159]. Several animal and human D2 contribute to the influx of eosinophils, CD4+ T lymphocytes, and studies are correlated with eosinophils mediated asthma development basophils by stimulation of expression of adhesion molecules on en- with an increase in IL-5 and IL-18 levels. Eosinophil mediated asthma in dothelial cells and cause severe allergic responses and nasal obstruc- humans account 20% with refractory asthma [160]. Increase in IL-5 tion. CD4+ lymphocytes represent IL-5 that also play a role in allergic levels observed in asthma patients with acute respiratory, viral, mixed rhinitis by activation of eosinopoiesis, influx, and survival of eosino- viral/bacterial, infections, pneumonia, bronchitis [161]. Increased IL- phils in nasal tissues [173–176]. 18 levels were observed in asthma patients and correlated with asthma Corticosteroids like fluticasone, mometasone, ciclesonide,

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Fig. 6. Eosinophils associated allergic diseases. triamcinolone, flunisolide, beclomethasone, betamethasone, anti- triggers for hives. Eosinophils are recruited upon allergen exposure in histamines like azelastine, olopatadine, chromones like sodium cro- urticaria and contribute to the pathogenesis by the release of proin- moglicate, nedocromil sodium, anticholinergics like ipratropium bro- flammatory cytokines, tissue-damaging protein, and immunoregulatory mide, decongestants like ephedrine, pseudoephedrine, xylometazoline; molecules. Eosinophilic granular proteins MBP and ECP observed in antihistamines like levocetirizine, cetirizine, desloratadine and lor- urticaria with IL-3, IL-4, IL-5, IL-2, IL-10, IL-12, and GM-CSF, IFN-γ, atadine, fexofenadine, acrivastine, rupatadine, carebastine and ebas- eosinophilic infiltration with deposits of cationic proteins MBP and EDN tine; corticosteroids like hydrocortisone, prednisolone; antileukotrienes and high levels of leukotrienes C4 are observed in the lesioned skin like montelukast and zafirlukast and leukotriene synthesis inhibitors [183]. Medications for urticaria include epinephrine auto-injector, an- like zileuton; decongestants like pseudoephedrine are advised as a tihistamines, ultraviolet therapy, application of hydrophobic barrier pharmacotherapy for allergic rhinitis. Apart from the medications im- creams, anti-IgE antibody Omalizumab administration [184–188]. munotherapy is also a cure for people with allergic rhinitis [177]. 9.7. Eosinophilia 9.5. Chronic hyperplastic eosinophilic sinusitis The condition where eosinophils count increases < 450 cells per μl Sinusitis is an inflammation of the sinuses that results in mucous of blood is eosinophilia [189]. Eosinophilia observed in a variety of formation. Acute sinusitis may be a result of allergens exposure and also allergic diseases that encountered as a result of increased eosinophil results in fever, sore throat, headache and swelling of the face. Chronic levels or cytokines such as IL-4, IL-5, and IL-13 that may also induce sinuses are severe disease process associated with nasal polyposis and eosinophilia. Transgenic mice expressing IL-5 show eosinophilia [190]. develop upon exposure with antigens, allergens, fungal, bacterial The diagnosis of eosinophilia in patients characterized by an allergic agents. Eosinophilic chronic rhinosinusitis is intractable and persistent condition like wheezing, rhinitis, or eczema [191]. The common factors disease and characterized by an inflammation of the nose and paranasal that contribute to eosinophilia include exposure to helminth like sinuses with nasal congestion and excessive mucus production and schistosomiasis; the presence of a pet dog infected with Toxocara canis, eosinophilic infiltration of nasal polyp tissue. IL-4, IL-5, or IL-1β may be and hypersensitivity to drugs. Eosinophilia observed in a variety of critical for PDGFRα and play a pivotal role in the pathophysiology of cancers [192,193]. Parasitic eradication is the main cure for eosino- eosinophilic and non-eosinophilic chronic rhinosinusitis with nasal philia and albendazole is popularly used [194]. Therapeutics for eosi- polyps [178]. IL-16 may stimulate the migration and persistence of nophilia with organ involvement include corticosteroids and IFN-α for activated eosinophilic granulocytes in eosinophilic chronic rhinosinu- the steroid-resistant disease. Other agents for the steroid-resistant dis- sitis [179]. Th2 mediated IL-25, IL-33, and IL-31, TGFα is up-regulated ease, which are usually given as long-term maintenance regimens to in eosinophilic chronic rhinosinusitis [180]. Higher leukotriene C4 le- control organ involvement, include the hydroxyurea, Chlorambucil, vels can be an indicator of the risk of recurrence of nasal polyps in Vincristine, Cytarabine, 2-Chlorodeoxyadenosine (2-CdA) Etoposide, patients with recurrent sinonasal polyps after surgery. Leukotriene re- Cyclosporine [195]. ceptor antagonists like montelukast and zafirlukast and the leukotriene synthesis inhibitor zileuton are recommended therapeutic measures 9.8. Eosinophilic esophagitis (EoE) [180,181]. Intranasal corticosteroids are also therapeutic strategies to modulate nasal mucosa, epithelial repair and regulating tissue re- EOE is one of the major cause of upper gastrointestinal morbidity modeling markers, and to reduce tissue eosinophil infiltration [182]. with an estimated prevalence of 56.7/100,000 persons. Food sensitization is one of the main reasons for EOE and characterized by eso- 9.6. Urticaria or hives phageal dysfunction with the formation of eosinophilic infiltrate in the esophageal mucosa [196]. Several eosinophils active Th2 cytokines, IL- Body’s reactions to allergens cause rashes on the skin that turn to 4, IL-5, IL-13, and IL-18 shown to increase in EoE patients, and the swollen pale red bumps that are itchy and sometimes causes burning, overexpression of these mice promotes disease pathogenesis similar to and the condition also referred to as hives. Food allergens, medications, the human. Our earlier study showed CD274 expressing and non-ex- exposure to cold or hot environmental conditions and insect stings are pressing eosinophils in pediatric and adult EoE patients. CD274

91 H.K. Kandikattu, et al. Cytokine and Growth Factor Reviews 47 (2019) 83–98 expression on blood eosinophils and blood mRNA expression levels level, erythrocyte sedimentation rate, C-reactive protein, and platelet were higher EoE patients and decreased following treatment [197]. counts [212,213]. Corticosteroid treatment with intravenous methyl- Therapeutic approaches for EoE include chronic dietary elimination of prednisolone or oral prednisone and omalizumab were considered an allergic food, topical corticosteroid application, and esophageal dilation effective strategy for EP [214,215]. [198]. Anti-IL-5, anti-IL-13 and anti-IL-4 Ra clinical trials are in progress in most of the allergic diseases including EoE. Currently, the 9.13. Hypereosinophilic syndrome (HES) elimination diet and corticosteroids therapy are the best approaches to improve the EoE patients quality of life [199]. HES is characterized by a marked increase in eosinophils (> 1500 eosinophils/mm3) and its associated pathology with eosinophil-medi- 9.9. Eosinophilic cystitis (EC) ated end-organ damage. HES is also associated with cardiovascular complications with endomyocardial fibrosis and thrombosis [216]. HES Eosinophilic cystitis characterized by infiltration of eosinophils and patients showed clonal T-cell receptor rearrangements and IL-5 pro- − inflammation across the bladder wall. EC is characterized by injury of ducing T cells characterized by CD3 CD4+ T cells [217]. HES also may eosinophils to the bladder tissues resulting in gross hematuria, marked be due to interstitial chromosomal deletion on 4q12 leading to the irritation of the lower urinary tract causing dysuria and frequency and creation of the FIP1L1-PDGFRA fusion gene (F/P+variant) [218]. fibrosis of the mucosa and muscularis necrosis of bladder wall [200]. Corticosteroids, hydroxyl urea, vincristine, prednisone, hydro- Dysregulation of clonal eosinophilic proliferation, resulting in over- xycarbamide, and interferon-α, mepolizumab (anti–IL-5 mAb), imatinib production eosinophils in bladder mucosa with an elevation of IL-4, IL- mesylate, cyclophosphamide, 6-thioguanine, methotrexate, cytarabine, 5, IL-13, IFNγ, and TNFα observed in EC. Cyclophilin inhibitors and, 2-CDA, alemtuzumab, cyclosporine, intravenous immunoglobulin are cyclosporine identified as a promising strategy to treat EC [201]. suggested therapy for HES [219,220].

9.10. Eosinophilic fasciitis (EF) 9.14. Eosinophilic COPD

EF characterized by edema and induration of the arms and legs and Chronic obstructive pulmonary disease is a lethal disease and is the infiltration of eosinophils. EF diagnosed as inflammation and thick- 4th leading cause of deaths worldwide (WHO 2015). IL-18 over- ening of collagen bundles in the superficial muscle fascia with in- expression is linked with emphysematous lesions and mediates Th1, filtration of immune cells. Laboratory diagnosis EF includes eosinophils Th2, and Th17 cytokine responses [221]. Increased expression of IL-18 accumulation in blood, hypergammaglobulinemia, and an increase in was observed in COPD patients and correlated with disease severity erythrocyte sedimentation rate [202]. An increase in T cell population [222–224]. Due to the pathogenic role of eosinophils in COPD clinical and IL-5 levels observed in EF patients, and the increase in IL-5 levels results demonstrated the benefits of monoclonal antibodies targeting IL- correlated with enhanced production of eosinophils, their maturation, 5 in severe eosinophilic COPD. Mepolizumab, a humanized monoclonal and recruitment to the inflamed regions [203–206]. Therapy for EF antibody, reduces eosinophil counts in blood and tissues by blocking IL- includes administration of corticosteroids and sulfasalazine, cyclos- 5, through binding to eosinophil surface receptors [67,225]. Mepoli- porine, methotrexate, hydroxychloroquine [207]. zumab at a dose of 100 mg was associated with a lower annual rate of moderate or severe exacerbations than placebo among patients with 9.11. Eosinophilic granulomatosis with polyangiitis (EGPA), aka Churg- COPD and an eosinophilic phenotype and suggested that eosinophilic Strauss syndrome airway inflammation contributes to COPD exacerbations [226].

EGPA is a systemic small‐vessel eosinophilic vasculitis observed in 9.15. Eosinophilic myocarditis (EM) association with asthma and eosinophilia. It is characterized by the presence of anti-myeloperoxidase (MPO), anti-neutrophil antibodies in EM is an acute life-threatening cardiac inflammatory disease that is the cytoplasm of 30–38% of patients and most frequently involves characterized by eosinophilic infiltration and has a poor prognosis and peripheral nerves and skin [208]. Apart from genetic background as- requires endomyocardial biopsy for definitive diagnosis. EM often ac- sociated with HLA-DRB4 alleles the disease can be triggered by ex- companied by eosinophilia and is associated with immune dysfunc- posure to allergens, infections, vaccinations or drugs such as macrolide tions. The clinical observation of patients with EM is with abrupt im- antibiotics, leukotriene receptor antagonists and exposure to particulate pairment of left ventricular ejection fraction and high risk of malignant silica. EGPA is a Th2 mediated disease and the T cells produced Th2 arrhythmias. Thus, corticosteroid therapy, some form of inotropes and cytokines such as IL-4, IL-13, IL-5, and CD294+ T cells observed with mechanical circulatory support for recovery in patients with EM was an increase in CCL17 and IL17A and a decrease in TREG cells. Clinical supportive and beneficial. Elevated IL-5 levels were observed in pa- manifestation and laboratory findings demonstrate asthma and rhi- tients with EM and anti-IL-5 therapy by administration of Mepolizumab no‐sinusitis, peripheral eosinophilia lung infiltrates due to bronchial improved cardiac function [227]. Despite the progress in understanding plugging by mucus formation is also observed in patients [209]. Cy- the EM further clinical trials and awareness of disease progress and clophosphamide, Methotrexate, Rituximab, Mepolizumab suggested treatment are required for treating patients with EM [228,229]. In- treatment strategy for EGPA [2010,211]. duction of EM in hypereosinophilic IL-5 Tg mice resulted in eosinophilic myocarditis with ventricular and atrial inflammation and progress to 9.12. Eosinophilic pneumonia (EP) dilated cardiomyopathy [137].

Eosinophilic pneumonia is a pulmonary disease characterized by 9.16. Eosinophilic cellulitis (ECE)/ Wells syndrome diffuse pulmonary infiltrates and an increase in eosinophils in the lungs and bronchoalveolar lavage fluid. EP’s are due to lung infections, or ECE also was known as Wells syndrome is a hypersensitivity of the drug-induced and off acute and chronic types. Several studies reported dermis against a variety of exogenous and endogenous antigenic stimuli that cigarette smoking linked with the development of acute eosino- and is usually seen in adults and rarely in children. ECE represents philic pneumonia. Chronic eosinophilic pneumonia characterized by acute pruritic dermatosis, with scarring and flame figures of the skin radiographic evidence of bilateral peripherally located opacities with with an accumulation of inflammatory cells and eosinophilic debris. IL- shortness of breath for several months. Peripheral blood eosinophilia 5 overproduction might contribute to eosinophil accumulation [230]. with blood eosinophil count > 1000/mL and increase in serum IgE CD4+CD7−T cells may be implicated in IL-5 production and

92 H.K. Kandikattu, et al. Cytokine and Growth Factor Reviews 47 (2019) 83–98 recruitment of dysregulated eosinophils in ECE [231]. IL-4 and IL-13 5 and GM-CSF accumulation observed along with eosinophil levels in mediated activation of CD163 + M2 macrophages might also con- EGE. Eotoxin associated eosinophil accumulation seen in lamina pro- tribute to the recruitment of eosinophils in ECE [232]. IL-2 mediated pria of stomach and intestine [247]. Treatment for EGE includes ad- platelet activation stimulated activation CD25 expressing eosinophils ministration of corticosteroids like fluticasone, prednisolone and bu- degranulation and release of eosinophilic cationic protein and tissue desonide and mast cell stabilizer cromolyn, leukotriene receptor damage documented in ECE [233]. Treatment measures of ECE include antagonists like montelukast [248]. corticosteroids, dapsone, antihistamines, colchicine, interferon‐α, an- timalarial drugs, and immunosuppressive agents like cyclosporine and 10. Conclusion and future perspectives azathioprine, and tacrolimus [234–237]. Eosinophils are normal constituents of the GI tract, mammary 9.17. Pulmonary eosinophilia (PE) glands, and bone marrow, and play roles in development and homeostasis of these organs. In the present review, we discussed the evolu- Following allergen exposure in pulmonary eosinophilia character- tion of the eosinophil as a multi-factorial leukocyte with pleiotropic ized by eosinophilia, goblet cell metaplasia, and increased Th1, Th2, functions, and the significance of IL-5, IL-18 and other cytokines in Th17 cells mediated cytokine production. Particularly, Th17 cells eosinophil associated allergic diseases. Although historically eosino- mediated IL-17 play a key role in immune reactions in pulmonary eo- phils are considered as cells that exhibit defense against parasites, the sinophilia following A. fumigatus exposure in mice. Inflammation atte- vast majority of data supports that eosinophils are pleiotropic multi- nuated in IL-17 knockout mice challenged with A. fumigatus with a functional leukocytes that promote allergy and allergic diseases and significant decrease in eosinophils, conidial clearance, and the early elicit innate and adaptive immune responses upon hyperactivity to al- transient peak of CD4+ CD25+ FoxP3+ cells was blunted explaining lergens. In Th2 type inflammation/allergy IL-4, IL-5, IL-9, IL-13, IL-18, the role for IL-17 in driving Th2-type inflammation to repeated in- IL-25, and IL-31 cytokines play a critical role. Several studies carried halation of fungal conidia [143]. Therapy for PE includes prednisolone, out in humans, and animal models of eosinophil allergic diseases re- methylprednisolone, and oral glucocorticoids, inhaled glucocorticoids vealed that among these cytokines IL-5 and IL-18 play a major role in [238]. The JAK-3 inhibitor CP-690550 acts as an anti-inflammatory eosinophil differentiation, maturation, development, transformation, agent for pulmonary eosinophilia in a mouse model [239]. migration, accumulation and elicit immune reactions. Small molecule antagonists of CCR3, CRTH2 or eosinophil inhibitory receptors might 9.18. Eosinophilic gastrointestinal disorders (EGID) also be an effective strategy to treat eosinophils in allergic diseases. Therapies with molecules that block IL-5 or and IL-18 signaling might EGID’s selectively affect the gastrointestinal tract with inflammation be promising to treat eosinophil-mediated allergic diseases. Although and accumulation of eosinophils in the absence of known causes for anti-IL-5 antibody therapy for allergic diseases remains elusive, a po- eosinophilia like drug reactions, parasitic infections, and malignancy. tential of humanized anti-human-IL-5Rα mAb treatment or anti-hIL- The common factors for EGID’s are genetic, food sensitization and 18Rα mAb treatment or in combination for asthmatic and allergic persons with EGID often have an atopic disease. EGID symptoms in- disease patients may be beneficial as a therapeutic strategy in the clude difficulty in swallowing, vomiting, reflux, abdominal and chest treatment to eliminate and control eosinophils and subsets of eosino- pain. IL-5, IL-13, and IL-18 implicated in the EGID pathogenesis. The philic phenotypes that mediate allergic diseases. Blockade of eosino- diagnosis for EGID is through biopsies from endoscopy and/or colo- phils production in bone marrow, transformation into pathogenic eo- noscopy [240,241]. The common EGID’s described below. sinophils, inhibition of eosinophil activation and factors that contribute to eosinophil apoptosis is also interesting strategies for eosinophil de- 9.18.1. Eosinophilic colitis (ECO) pletion in allergic diseases. In summary, we propose the initiation of the It’s a rare form of the eosinophilic gastrointestinal disease and ob- anti-IL-18 clinical trial to block the transformation of naïve eosinophils served in neonates and also in young adults. The pathophysiology as- into the pathogenic eosinophils. Anti-IL-18 therapy may maintain the sociated with ECO is altered hypersensitivity and associated with food eosinophils associated innate immunity and restrict disease pathogen- allergy in infants, and in adults, it is T lymphocyte-associated. Common esis by restricting the maturation of pathogenic eosinophils. Thus, we symptoms include abdominal pain, weight loss, and diarrhea, mucosal need additional studies using genetically engineered IL-5 and IL-18 injury and malabsorption [242]. ECO characterized by eosinophilic double gene-deficient mice for in vivo, characterization of the im- infiltration in the colon, which is also associated with high serum IgE, munobiology eosinophils associated disease pathogenesis. and IL-5 levels. Treatment for ECO includes administration with glucocorticoids, antihistamines, leukotriene receptors antagonists and Conflict of interest drugs that target IL-5 and IgE levels [243]. No author has any conflict of interest. 9.18.2. Eosinophilic gastritis (EG) EG is commonly confined to stomach eosinophilic inflammation; Acknowledgments however it also represents coexisting eosinophilic accumulation in the esophagus. Blood eosinophil counts, and accumulation of MIB-1+, Dr. Mishra is the Endowed Schlieder Chair; therefore, authors thank CD117+ mast cells, and FOXP3+ T-reg cells, activated T cells, are in- Edward G. Schlieder Educational Foundation for the support. The work creased in patients with EG. Cytokine-like IL-4, IL-5, IL-13, IL-17, IL-18 is partially supported, by NIH R01 AI080581 grant funding (AM). and CCL26 was also significantly increased in EG patients that may correlate with elevated eosinophil levels or vice versa [244]. Therapies References for EG include a dietary restriction in patients allergic to milk, egg, soy, wheat, nuts, seafood, red meats and other foods [245]. [1] P.C. Fulkerson, M.E. Rothenberg, Eosinophil development, disease involvement, and therapeutic suppression, Adv. Immunol. 138 (2018) 1–34. [2] S.U. Venkateshaiah, A. Mishra, M. Manohar, A.K. Verma, P. Rajavelu, R. Niranjan, 9.18.3. Eosinophilic gastroenteritis L.G. Wild, N.A. Parada, U. Blecker, J.A. Lasky, A. 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Levy, Wells’ syndrome Dr. Anil Mishra, PhD is Edward G. Schlieder Educational associated with parvovirus in a 5-year old boy, Pediatr. Dermatol. 29 (6) (2012) Foundation Endowed Chair and Professor of Medicine. He 762–764. is also the Director of Tulane Eosinophilic Disorder Center [236] A.E. Gilliam, A.L. Bruckner, R.M. Howard, B.P. Lee, S. Wu, I.J. Frieden, Bullous in the Section of Pulmonary Diseases at Tulane University "cellulitis" with eosinophilia: case report and review of Wells’ syndrome in School of Medicine. Dr. Mishra's research established that childhood, Pediatrics 116 (1) (2005) e149–55. eosinophils are the resident cells of the gastrointestinal [237] T. Ohtsuka, Oral tacrolimus treatment for refractory eosinophilic cellulitis, Clin. tract that home prenatally (Mishra et al., J. Clin. Exp. Dermatol. 34 (8) (2009) e597–8. Invest.1999). He showed that eosinophil active chemokine fi [238] U. Katz, Y. Shoenfeld, Pulmonary eosinophilia, Clin. Rev. Allergy Immunol. 34 (3) eotaxin-1 constitutively expressed and has signi cant role (2008) 367–371. for eosinophils homing into the gastrointestinal tract. He fi [239] E. Kudlacz, M. Conklyn, C. Andresen, C. Whitney-Pickett, P. Changelian, The JAK- developed the rst murine model of eosinophilic esopha- fi 3 inhibitor CP-690550 is a potent anti-inflammatory agent in a murine model of gitis (EoE) (Mishra et al., J. Clin. Invest. 2001). His ndings pulmonary eosinophilia, Eur. J. Pharmacol. 582 (1–3) (2008) 154–161. implicated aeroallergen in the etiology of EoE and sug- fl [240] M.E. Rothenberg, Eosinophilic gastrointestinal disorders (EGID), J. Allergy Clin. gested that esophageal eosinophilic in ammation is mechanistically regulated by IL-5, IL- Immunol. 113 (1) (2004) 11–28 quiz 29. 13 and eotaxin (J. Immunology 2002, and Gastroenterology, 2003). Furthermore, we also [241] A. Straumann, Eosinophil-associated gastrointestinal disorders, Clin. Immunol. indicated that T cell subset iNKT cells are critical and the source of eosinophil active (2019) 633–640. cytokines in human EoE, and targeting the cell surface receptors of iNKT cells improve [242] A.A. Alfadda, M.A. Storr, E.A. Shaffer, Eosinophilic colitis: epidemiology, clinical EoE in experimental model of EoE (Clinical and Translational Immunology, 2014). Most features, and current management, Ther. Adv. Gastroenterol. 4 (5) (2011) recently, the laboratory of Dr. Mishra has reported that rIL-15 is a therapeutic molecule fi 301–309. for the allergen-induced airway hyperactivity and brosis for chronic asthma and other [243] V. Uppal, P. Kreiger, E. Kutsch, Eosinophilic gastroenteritis and colitis: a com- pulmonary functional impairment (J. Allergy Clin. Immunol. 2017). Dr. Mishra is an prehensive review, Clin. Rev. Allergy Immunol. 50 (2) (2016) 175–188. elected fellow of the American Academy of Allergy Asthma Immunology (FAAAAI) and [244] J.M. Caldwell, M.H. Collins, E.M. Stucke, P.E. Putnam, J.P. Franciosi, J.P. Kushner, the American Gastrointestinal Association (FAGA). He has published over 85 articles, J.P. Abonia, M.E. Rothenberg, Histologic eosinophilic gastritis is a systemic dis- book chapters and reviews on molecular mechanisms of pulmonary and gastrointestinal, ’ order associated with blood and extragastric eosinophilia, TH2 immunity, and a allergic responses in high impact factor journals. Dr. Mishra research is supported by unique gastric transcriptome, J. Allergy Clin. Immunol. 134 (5) (2014) TheNational Institutes of Health via NIDDK and NIAID institutes Dr Mishra is also a 1114–1124. member of several NIH study sections and serving Editor and Editorial Board member in a [245] H.M. Ko, R.A. Morotti, O. Yershov, M. Chehade, Eosinophilic gastritis in children: number of international journals. clinicopathological correlation, disease course, and response to therapy, Am. J.